NEW ORLEANS – A single 300-mg injection of inclisiran, a novel non–monoclonal antibody PCSK9 inhibitor, plus statin therapy, achieved a mean 51% reduction in LDL cholesterol, compared with placebo plus a statin, an effect sustained for 90 days.
Moreover, a second subcutaneous 300-mg dose given at day 90 resulted in a 57% reduction in LDL sustained at day 180 with a highly favorable safety profile in the phase II ORION-1 study, Kausik K. Ray, MD, reported at the American Heart Association scientific sessions.
“The efficacy, safety and dosing profile of inclisiran are likely to ensure significant and durable reductions in LDL-C and thus could potentially impact cardiovascular outcomes,” said Dr. Ray, professor of public health at Imperial College London.
Inclisiran is a synthetic RNA interference agent. After injection it selectively goes to the liver, bypassing other tissues and thereby limiting toxicity. Inclisiran halts PCSK9 protein synthesis in the liver, with a resultant sharp, steep, and sustained drop in LDL levels.
Inclisiran achieves LDL lowering of a magnitude similar to that of the PCSK9-inhibiting monoclonal antibodies alirocumab (Praluent) and evolocumab (Repatha), but it will be less expensive to produce and far less costly to administer than the monoclonal antibodies. Dosing is planned to be two or three injections per year, rather than every 2 or 4 weeks, as with the PCSK9 inhibitor monoclonal antibodies, which cost a hefty $14,000 per year. And the sustained efficacy of a dose of inclisiran should make patient adherence to LDL-lowering therapy less of an issue, Dr. Ray continued.
ORION-1 (Inhibition of PCSK9 Synthesis Via RNA Interference) was a double-blind, randomized, placebo-controlled trial comprising 501 patients already on maximally tolerated statin therapy for atherosclerotic cardiovascular disease or at high risk. Nevertheless, their baseline LDL was 125-135 mg/dL. Participants were randomized to one of six doses of inclisiran or placebo. At 90 days they received a second dose. Dr. Ray presented 90- and 180-day outcomes.
This was primarily a safety and dose-ranging study. Side effects at 90 days were no different from placebo regardless of whether patients received 100, 200, 300, or 500 mg of inclisiran. There was no signal of a problem with myalgia or elevated liver enzymes. Mild injection site reactions lasting for more than 4 hours occurred in 1.5%-3.3% of inclisiran-treated patients, but not in a dose-dependent fashion.
One 300-mg dose of inclisiran, in addition to achieving a mean 51% reduction in LDL from baseline at day 90, resulted in a mean 28% reduction in total cholesterol, a modest 10% drop in triglycerides, a 9% increase in HDL, a 37% drop in Apo-B, and a median 23% reduction in Lp(a). Plasma PCSK9 levels plunged in parallel with LDL.
The mean drop in LDL from baseline at day 180 after two 300-mg doses of inclisiran spaced 90 days apart was 65 mg/dL. The LDL reduction ranged from a minimum of 26.5 mg/dL to a maximum of 122 mg/dL.
Dr. Ray’s presentation of the ORION-1 findings followed on the heels of publication of a positive but much smaller phase I study of inclisiran (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1609243).
A large phase II clinical trial with cardiovascular outcomes is planned.
Discussant Borge G. Nordestgaard, MD, could find no fault with ORION-1 or inclisiran’s performance to date.
Bruce Jancin/Frontline Medical News
Dr. Borge G. Nordestgaard
“A 50%-60% reduction in LDL lasting for 3-6 months, with two or three injections per year – it seems fantastic. And there don’t seem to be side effects except for mild injection site reactions. It looks really, really encouraging, I must say,” said Dr. Nordestgaard, professor of genetic epidemiology at the University of Copenhagen.
“I think the key question is, will the very impressive LDL reduction that we see now be sustainable over time in the longer phase III trials,” he added.
Dr. Ray reported serving as a consultant to the Medicines Company, which together with Alnylam Pharmaceuticals sponsored ORION-1, and receiving research grants from and/or serving as a consultant to more than half a dozen other pharmaceutical companies.
Dr. Ray discussed his findings in a video interview at the meeting.